RESUMO
A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Tiazóis/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Haplorrinos , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética , Proteínas não Estruturais Virais/metabolismoRESUMO
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
Assuntos
Antivirais/síntese química , Hepacivirus/efeitos dos fármacos , Pirrolidinonas/química , Tiazinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Sítios de Ligação , Cristalografia por Raios X , Pirrolidinonas/síntese química , Pirrolidinonas/farmacocinética , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismoRESUMO
A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.